Optimal Regimen for Methotrexate and Folic Acid

It is common practice for doctors to prescribe folic acid for their rheumatoid arthritis patients who are treated with methotrexate. Folic acid is depleted by methotrexate, so it must be replenished through supplementation. Folic acid is needed to prevent red blood cell abnormalities and anemia. It also has been seen to reduce nausea from methotrexate.

Methotrexate is the most commonly prescribed DMARD (disease modifying anti-rheumatic drug) for rheumatoid arthritis and other rheumatic conditions. Methotrexate is available in oral and injectable formulations. Either way, methotrexate is usually administered once a week (on the same day every week).

What Medical Resources Say About Folic Acid

There is variability in whether doctors prescribe a daily dose of 1 milligram of folic acid or a larger dose once a week. The larger dose is usually given the day after the methotrexate dose. Sometimes doctors advise their patients to skip the daily dose on the day of their methotrexate dose.

The National Rheumatoid Arthritis Society in the UK, "Methotrexate depletes the body of folic acid and the frequency of side effects can be reduced by taking supplements of folic acid. This can be taken as 5 to 10 milligrams weekly. Taking higher doses may reduce the efficacy of methotrexate and most rheumatologists recommend taking the folic acid one or two days after the methotrexate, and in particular not taking it on the same day as the methotrexate."

The different treatment schedules with folic acid can lead to questions as to what is the right one. Rheumatologist Scott Zashin, a clinical assistant professor at the University of Texas Southwestern Medical School says, "I have my patients take it daily, including the day of methotrexate. I think either is fine—including it or skipping it the day of. It has not been studied, but it is unlikely that either protocol is harmful."

Conclusions From the Cochrane Review

An editorial about a 2013 Cochrane review of studies of the use of folic acid with methotrexate pointed out that folic acid use is quite variable. Some doctors prescribe folic acid to be used regularly by patients taking methotrexate, while other doctors prescribe it only to patients with side effects from methotrexate. Still, others don't prescribe it at all because they believe folic acid reduces the effectiveness of methotrexate.

The review, based on results from six randomized clinical trials, supported the use of low-dose folic acid in rheumatoid arthritis patients treated with methotrexate. Folic acid supplementation reduced gastrointestinal toxicity and liver enzyme elevation.

The editorial suggested that folic acid 1 milligram daily is the most common utilization of the supplement for methotrexate-treated patients.

The review and subsequent editorial also raised questions as to whether patients should take folic acid the rest of their lives, and whether higher doses are beneficial or can interfere with methotrexate. It was concluded that the dose-effect association will require more study.

The Bottom Line

There are various acceptable protocols for taking folic acid when being treated with methotrexate, and further studies may show one is preferable. Discuss it further with your doctor to understand why she chooses one over the other.

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  1. Shea B, Swinden MV, Tanjong Ghogomu E, Ortiz Z, Katchamart W, Rader T, et al. Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis. Cochrane Database of Systematic Reviews 2013;5:CD000951. doi:10.1002/14651858.CD000951.pub2

  2. Singh JA. Folic acid supplements for rheumatoid arthritis patients taking methotrexate: the good gets better (editorial). Cochrane Database of Systematic Reviews 2013;7:ED000063. doi:10.1002/14651858.ED000063

  3. Butler R. Methotrexate in Rheumatoid Arthritis. National Rheumatoid Arthritis Society.

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